Selective ligands for tau aggregates

Abstract

The invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or carbamate thereof, or a salt of such an ester or carbamate, wherein either: R 1 is OH, and R 2 is H; or R 1 is H, and R 2 is OH. The invention further provides uses of the compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration.

1 .- 17 . (canceled) 
     
     
         18 . A method for preparing a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein either:
 R 1  is OH, and R 2  is H; or 
 R 1  is H, and R 2  is OH; 
 
         the method comprising:
 (a) reacting a compound of formula (A): 
 
       
       
         
           
           
               
               
           
         
         with a compound of formula (B): 
       
       
         
           
           
               
               
           
         
         wherein either:
 R 1A  is OSi(CH 3 ) 3 , and R 2  is H; or 
 R 1B  is H, and R 2  is OSi(CH 3 ) 3  and 
 (b) deprotecting the product of step (a). 
 
       
     
     
         19 . The process of  claim 18 , further comprising treating a compound of formula (C): 
       
         
           
           
               
               
           
         
         with NBS to provide the compound of formula (A). 
       
     
     
         20 . The process of  claim 19 , further comprising treating 2,6-difluoropyridine with 3-methoxypiperidine to provide the compound of formula (C). 
     
     
         21 . A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein either:
 R 1  is OH, and R 2  is H; or 
 R 1  is H, and R 2  is OH. 
 
       
     
     
         22 . The method of  claim 21 , wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, Creutzfeldt-Jacob disease, familial Alzheimer's disease, argyrophilic grain disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinsonism linked to chromosome 17, postencephalitic Parkinsonism, Guadeloupean parkinsonism, globular glial tauopathies, ageing-related tau astrogliopathy, Parkinsonism-dementia complex of Guam, Niemann-Pick disease type C, myotonic dystrophy, inclusion-body myositis, chronic traumatic encephalopathy, Down's syndrome, Gerstman-Sträussler-Scheinker syndrome, British dementia, familial Danish dementia, dementia pugilistica, tangle predominant senile dementia, Huntington's disease, Lewy body disorders, Prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangles with calcification, neurodegeneration with brain iron accumulation, mutation affecting the sodium/proton exchanger, cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene, TARDBP mutation p.Ile383Val associated with semantic dementia, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallido-ponto-nlgral degeneration, progressive subcortical gliosis, tangle only dementia, myotonic dystrophy, tau panencephalopathy, AD-like with astrocytes, Gerstmann-Sträussler-Scheinker with tau, mutations in LRRK2, SLC9A6-related mental retardation, and white matter tauopathy with globular glial inclusions. 
     
     
         23 . The method of  claim 22 , wherein the disease or disorder is Alzheimer's disease. 
     
     
         24 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein either:
 R 1  is OH, and R 2  is H; or 
 R 1  is H, and R 2  is OH. 
 
       
     
     
         25 . A compound of  claim 24 , of formula (Ia) or (Ib): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . A compound of  claim 24 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . A compound of  claim 24 , which is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.